On Cancer: Immune Cells in the Brain Could be Enlisted to Fight Glioblastoma

This image shows part of a glioblastoma tumor from a mouse treated with a CSF-1R inhibitor. The drug was shown to induce tumor-associated macrophages (green) to phagocytose or eat tumor cells (red).

White blood cells called macrophages patrol almost every tissue of the body to gobble up bacteria, dead cells, and other waste. About ten percent of the cells in the brain are macrophages, also known as microglia. These cells have many important functions such as protecting against infections and repairing damaged nerve tissue but have also been shown to promote brain diseases including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.

Now a recent study led by Memorial Sloan Kettering scientists reveals that macrophages can support the growth and progression of glioblastomabrain tumors – the commonest and most deadly form of primary brain cancer – and that it might be possible to control the disease by manipulating these cells with a drug. The research was done in mice and published in the October issue of the journal Nature Medicine.

Complex Tumors

Less than five percent of people with glioblastoma survive longer than five years after they are diagnosed even if they undergo intensive treatment with surgery, chemotherapy, or radiation. “There’s a crucial need for better strategies to control these aggressive tumors,” Dr. Joyce emphasizes.

So far scientists have had little success in developing targeted drugs against glioblastoma cells – drugs that home in on specific genetic mutations or biological pathways. “This is partly because glioblastoma tumors are very heterogeneous,” Dr. Joyce explains, referring to the fact that these tumors contain a highly diverse set of cancer cells with different genetic attributes.

In contrast, tumor-associated macrophages – which often make up as much as one third of the total tumormass – tend to be more biologically uniform and could therefore be easier to target. Dr. Joyce and her colleagues looked at these cells in mouse models of a subtype of the disease called proneural glioblastoma. They noticed that the more advanced a tumor was, the more infiltrated by macrophages it tended to be.

“A similar pattern has been found when samples of tumor tissue from patients were analyzed,” Dr. Joyce says. “It seemed as if the tumor-infiltrating macrophages were helping the cancer advance.”

The investigators set out to test what would happen if the mouse proneural glioblastoma tumors were depleted of macrophages. They treated the mice with a drug that has been shown to eradicate macrophages in the brain and other organs. It works by inhibiting CSF-1R, a protein known to be essential for macrophage survival.

Surprise Findings

“There were a couple of surprises,” Dr. Joyce says. The first was how striking the drug’s effect was. It stopped newly formed tumors from progressing, caused more-established tumors to shrink, and made the mice live significantly longer.

The second surprise was no less positive, but initially confounding to the researchers. “We thought CSF-1R inhibition would wipe out the tumor-associated macrophages,” Dr. Joyce explains. “But when we looked at the tumors of mice who had been treated, the macrophages were still there” even though the drug had killed macrophages in the surrounding, normal brain tissue.

The researchers found that the macrophages residing in tumors had not succumbed to the drug because certain proteins secreted by the tumors were keeping them alive. But the therapy changed the macrophages’ behavior, blunting their tumor-promoting functions while making them more prone to elicit an anti-tumor response.

For example, these macrophages were induced to attack tumors by “eating” glioblastoma cells, a process known as phagocytosis.

“Our research suggests CSF-1R inhibition actually re-educates macrophages to attack tumor cells rather than support their growth,” Dr. Joyce says. “This is intriguing because if tumor-associated macrophages could be manipulated in the same way in the clinic – and be enlisted to actively fight a person’s cancer – this might ultimately be a more effective therapeutic strategy than to deplete the cells.”

Bringing Macrophage-Targeting Therapies to Patients

There could be several other advantages to developing glioblastoma drugs that act on macrophages and using these drugs in combination with existing therapies such as chemotherapy or radiation.

CSF-1R inhibitors are currently being tested in early-stage clinical trials of glioblastoma patients and could be applicable in other diseases as well. “Studies have shown that in several cancer types, including breast, ovarian, thyroid, and pancreaticneuroendocrine tumors, increased numbers of tumor-associated macrophages correlate with poor patient prognosis, so it would be logical to test the drug in these diseases as well,” Dr. Joyce notes.

This research was funded by the Cycle for Survival, the Brain Tumor Centerat Memorial Sloan Kettering, the National Institutes of Health under grants CA126518 and CA148967, and other sources.

Nancy, thank you for writing. We are sorry to hear about your son's illness. BKM120 does not act in the same way as the drug used in this study. It belongs to a family of drugs called PI3 kinase inhibitors, which target tumor cells.

Hello, I am past surgery - 90% actually removed, 2 cycles of termodar - Oct 14th MRI showed growth in Tumor (that were just a hint in the previous scans). I am suppose to start on Avastin. I am looking for a good clinical trial with Avastin. Any suggestion?

Dear Vic, While we cannot give medical advice to individuals on the blog, we do have several clinical trials involving Avastin as well as other therapies. Please go to this link and search for bevacizumab (the generic name for Avastin), or by the disease type (e.g., brain tumors, primary): www.mskcc.org/cancer-care/clinical-trials/clinical-trial. If any of these trials seem right for you, the number to call is listed there. You can also search for trials through the National Cancer Institute: www.cancer.gov/clinicaltrials. Thanks for your comment, and we wish you all the best.
.

Our 3 year old granddaughter has undergone surgery and chemotherapy for neuroblastoma. Three tumors remain in her skull's bone structure but appear to have low activity. Would your current study have any possible application to her condition?

George, we are sorry to hear about your granddaughter. We are unable to answer individual medical questions on our blog. If you'd like to make an appointment for her to see someone in our Department of Pediatrics, you can call 212-639-5954. Thank you for your comment.

Submitted by Lisa Furkas | Monday, November 18, 2013 - 3:30 AM.

My 52 year old has been diagnosed with a GBM stage 4. Currently going through radiation and tremodar . Tumor is midbrain tectorial section. His sneak peek MRI is weds and I was wondering what my options would be at Sloan Kettering. I presume the oncologist is going to use avastin next. I am his care giver and want him to fight and win!

I am so happy to hear of ongoing research into this type of brain tumor. My son was diagnosed in 1987 with DIPG and passed in 1988, a month before his 5th birthday. At the time he was diagnosed we were told that this tumor had been researched for over 20 years with still no known reason for it and no known cure. Keep up the good work!!!!! God bless you!!!

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aggressive (uh-GREH-siv)

In medicine, describes a tumor or disease that forms, grows, or spreads quickly. It may also describe treatment that is more severe or intense than usual.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

Avastin (uh-VAS-tin)

A drug used to treat glioblastoma (a type of brain cancer) and certain types of colorectal cancer, lung cancer, and kidney cancer. It is also being studied in the treatment of other types of cancer. Avastin binds to a protein called vascular endothelial growth factor (VEGF). This may prevent the growth of new blood vessels that tumors need to grow. It is a type of antiangiogenesis agent and a type of monoclonal antibody. Also called bevacizumab.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

bacteria (bak-TEER-ee-uh)

A large group of single-cell microorganisms. Some cause infections and disease in animals and humans. The singular of bacteria is bacterium.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

bevacizumab (beh-vuh-SIH-zoo-mab)

A drug used to treat glioblastoma (a type of brain cancer) and certain types of colorectal cancer, lung cancer, and kidney cancer. It is also being studied in the treatment of other types of cancer. Bevacizumab binds to a protein called vascular endothelial growth factor (VEGF). This may prevent the growth of new blood vessels that tumors need to grow. It is a type of antiangiogenesis agent and a type of monoclonal antibody. Also called Avastin.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

biological (BY-oh-LAH-jih-kul)

Pertaining to biology or to life and living things. In medicine, refers to a substance made from a living organism or its products. Biologicals may be used to prevent, diagnose, treat or relieve of symptoms of a disease. For example, antibodies, interleukins, and vaccines are biologicals. Biological also refers to parents and children who are related by blood.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

blood (blud)

A tissue with red blood cells, white blood cells, platelets, and other substances suspended in fluid called plasma. Blood takes oxygen and nutrients to the tissues, and carries away wastes.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cancer (KAN-ser)

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

chemotherapy (KEE-moh-THAYR-uh-pee)

Treatment with drugs that kill cancer cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

clinical (KLIH-nih-kul)

Having to do with the examination and treatment of patients.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

clinical trial (KLIH-nih-kul TRY-ul)

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

drug (drug)

Any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

drug resistance (... reh-ZIH-stunts)

The failure of cancer cells, viruses, or bacteria to respond to a drug used to kill or weaken them. The cells, viruses, or bacteria may be resistant to the drug at the beginning of treatment, or may become resistant after being exposed to the drug.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

family history (FA-mih-lee HIH-stuh-ree)

A record of the relationships among family members along with their medical histories. This includes current and past illnesses. A family history may show a pattern of certain diseases in a family. Also called family medical history.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

generic (jeh-NAYR-ik)

Official nonbrand names by which medicines are known. Generic names usually refer to the chemical name of the drug.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

genetic (jeh-NEH-tik)

Inherited; having to do with information that is passed from parents to offspring through genes in sperm and egg cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

genetics (jeh-NEH-tix)

The study of genes and heredity. Heredity is the passing of genetic information and traits (such as eye color and an increased chance of getting a certain disease) from parents to offspring.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

glioblastoma (GLEE-oh-blas-TOH-muh)

A fast-growing type of central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord and has cells that look very different from normal cells. Glioblastoma usually occurs in adults and affects the brain more often than the spinal cord. Also called GBM, glioblastoma multiforme, and grade IV astrocytoma.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

hereditary (huh-REH-dih-tayr-ee)

Transmitted from parent to child by information contained in the genes.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

heterogeneous (HEH-teh-roh-JEE-nee-us)

Made up of elements or ingredients that are not alike.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

kinase (KY-nays)

A type of enzyme that causes other molecules in the cell to become active. Some kinases work by adding chemicals called phosphates to other molecules, such as sugars or proteins. Kinases are a part of many cell processes. Some cancer treatments target certain kinases that are linked to cancer.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

macrophage (MA-kroh-fayj)

A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

mass (mas)

In medicine, a lump in the body. It may be caused by the abnormal growth of cells, a cyst, hormonal changes, or an immune reaction. A mass may be benign (not cancer) or malignant (cancer).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

medicine (MEH-dih-sin)

Refers to the practices and procedures used for the prevention, treatment, or relief of symptoms of a diseases or abnormal conditions. This term may also refer to a legal drug used for the same purpose.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

MRI

A procedure in which radio waves and a powerful magnet linked to a computer are used to create detailed pictures of areas inside the body. These pictures can show the difference between normal and diseased tissue. MRI makes better images of organs and soft tissue than other scanning techniques, such as computed tomography (CT) or x-ray. MRI is especially useful for imaging the brain, the spine, the soft tissue of joints, and the inside of bones. Also called magnetic resonance imaging, NMRI, and nuclear magnetic resonance imaging.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

multiple sclerosis (MUL-tih-pul skleh-ROH-sis)

A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid), serving as a nerve insulator and helping in the transmission of nerve signals.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

nerve (nerv)

A bundle of fibers that receives and sends messages between the body and the brain. The messages are sent by chemical and electrical changes in the cells that make up the nerves.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

neuroblastoma (NOOR-oh-blas-TOH-muh)

Cancer that arises in immature nerve cells and affects mostly infants and children.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

pancreatic (PAN-kree-A-tik)

Having to do with the pancreas.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

phagocytosis (FA-goh-sy-TOH-sis)

The process by which a phagocyte (a type of white blood cell) surrounds and destroys foreign substances (such as bacteria) and removes dead cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

physician (fih-ZIH-shun)

Medical doctor.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

prognosis (prog-NO-sis)

The likely outcome or course of a disease; the chance of recovery or recurrence.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

progression (pruh-GREH-shun)

In medicine, the course of a disease, such as cancer, as it becomes worse or spreads in the body.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

protein (PROH-teen)

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiation (RAY-dee-AY-shun)

Energy released in the form of particle or electromagnetic waves. Common sources of radiation include radon gas, cosmic rays from outer space, medical x-rays, and energy given off by a radioisotope (unstable form of a chemical element that releases radiation as it breaks down and becomes more stable).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

referral (reh-FER-ul)

In medicine, the act of a doctor in which a patient is sent to another doctor for additional healthcare services.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

Referral

The approval form you receive from your primary care physician for you to see a specialist or get certain services. In many managed care plans, you need to get a referral form before you get care from anyone except your primary care doctor. If you do not first get a referral, the plan may not pay for your care. Patients in HMO plans must also obtain authorization for treatment from the carrier prior to an appointment at an out-of-network facility.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

response (reh-SPONTS)

In medicine, an improvement related to treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

surgery (SER-juh-ree)

A procedure to remove or repair a part of the body or to find out whether disease is present. An operation.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

therapeutic (THAYR-uh-PYOO-tik)

Having to do with treating disease and helping healing take place.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

therapy (THAYR-uh-pee)

Treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tissue (TIH-shoo)

A group or layer of cells that work together to perform a specific function.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tumor (TOO-mer)

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancer), or malignant (cancer). Also called neoplasm.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

will (wil)

A legal document in which a person states what is to be done with his or her property after death, who is to carry out the terms of the will, and who is to care for any minor children.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)